Methamphetamine abuse and dependence has rapidly become a major health problem throughout the United States. However, basic and clinical understanding of the neurobiology and treatment of methamphetamine addiction has lagged behind research on other drugs of abuse. This proposal endeavors to ameliorate this dearth of knowledge and proposes the development of a Translational Research in Addiction Center (TRAC) focused on the Clinical Neurobiology of Methamphetamine Dependence at the Medical University of South Carolina. Over the next four years, we will develop integrated, multidisciplinary teams to explore the neural pathways, cognitive and behavioral toxicities, and potential treatments for methamphetamine addiction in preparation for the submission of a P50 application. The TRAC is integrated around the common theme of translational research on methamphetamine addiction and will employ a well-established animal model of relapse in conjunction with a clinical laboratory and imaging center in an innovative collaboration designed to directly test hypotheses derived from the animal model in human subjects. In turn, information derived from methamphetamine dependent subjects in the clinical laboratory will inform and guide new directions in the animal models. The TRAC will determine the neurobiological adaptations mediating relapse and cognitive function at many levels of analysis, including cellular, physiological, and behavioral. We will also characterize in both preclinical and clinical models the neural circuitry of extinction training related to methamphetamine-associated cues and the relationship of cognitive deficits to drug-seeking behaviors. Importantly, neurobiological information derived from all of these projects will be used to develop rational pharmacological treatments designed to decrease relapse, improve methamphetamine-induced cognitive deficits, and facilitate extinction training. Thus, the TRAC will allow for the development of a multidisciplinary, integrated research team capable of conducting a multidimensional analysis of the clinical neurobiology underlying methamphetamine addiction and relapse. As part of the Center, a comprehensive plan has been established for mentoring new faculty and trainees and developing campus wide translational research in addiction. It is proposed that the integration and synergy inherent in the TRAC infrastructure that will be developed during the P20 funding period will provide the optimal opportunity for identifying novel pharmacological interventions that will be effective in treating methamphetamine addiction and reducing the individual and public health consequences of this devastating illness.